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A modified hTERT promoter-directed oncolytic adenovirus replication with concurrent inhibition of TGFβ signaling for breast cancer therapy

Cancer Gene Therapy volume 17, pages 235–243 (2010)Cite this article

A Corrigendum to this article was published on 15 November 2010

Abstract

We were interested in developing oncolytic adenoviral vectors that can be administered systemically for the treatment of breast cancer. To restrict viral replication in breast tumor cells, we constructed mhTERTAd.sTβRFc, a 01/07-based adenoviral vector expressing the soluble form of transforming growth factor-β (TGFβ) receptor II fused with the human Fc IgG1 (sTGFβRIIFc) gene, in which viral replication is under the control of a modified human telomerase reverse transcriptase (mhTERT) promoter. In addition, mhTERTAd.sTβRFc-mediated sTGFβRIIFc production targets the TGFβ pathway known to contribute to the tumor progression of breast cancer metastasis. We chose to use the mhTERT promoter because it was found to be relatively more active (approximately 20 times) in breast cancer cells compared with normal human cells. We showed that infection of MDA-MB-231 and MCF-7 breast cancer cells for 48 h with mhTERTAd.sTβRFc produced high levels of sTGFβRIIFc (greater than 1 μg ml−1) in the medium. Breast cancer cells produced nearly a 6000-fold increase in viral titers during the 48 h infection period. However, mhTERTAd.sTβRFc replication was attenuated in normal cells. Infection of breast cancer cells with a replication-deficient virus Ad(E1−).sTβRFc also produced high levels of sTGFβRIIFc, but under these conditions, no detectable viral replication was observed. Adenoviral-mediated production of sTGFβRIIFc was shown to bind with TGFβ-1, and to abolish the effects of TGFβ-1 on downstream SMAD-3 phosphorylation. The administration of mhTERTAd.sTβRFc intravenously into MDA-MB-231 human xenograft-bearing mice resulted in a significant inhibition of tumor growth and production of sTGFβRIIFc in the blood. Conversely, intravenous injection of Ad(E1−).sTβRFc did not show a significant inhibition of tumor growth, but resulted in sTGFβRIIFc in the blood, suggesting that viral replication along with sTGFβRIIFc protein production is critical in inducing the inhibition of tumor growth. These results warrant future investigation of mhTERTAd.sTβRFc as an antitumor agent in vivo.

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Acknowledgements

We thank Dr Janardan D Khandekar for his support of this research. We also thank Dr ZG Wang and Murali Ramachandra for their help, and Monica Tsang (R&D Systems) for providing the sTGFβRIIFc gene. This study was supported by NIH Grant R01CA127380 (P Seth).

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Authors and Affiliations

  1. Department of Medicine, Gene Therapy Program, Evanston Hospital, NorthShore Research Institute, Northwestern University, Evanston, IL, USA

    Z Hu, J S Robbins, A Pister, M B Zafar, Z-W Zhang, J Gupta, K J Lee, K Neuman & P Seth

  2. Yunsei University College of Medicine, Seoul, Korea

    C-O Yun

  3. Division of Endocrinology and Metabolism, Department of Medicine, University of Virginia, Charlottesville, VA, USA

    T Guise

Authors
  1. Z Hu
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  2. J S Robbins
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Correspondence to P Seth.

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Hu, Z., Robbins, J., Pister, A. et al. A modified hTERT promoter-directed oncolytic adenovirus replication with concurrent inhibition of TGFβ signaling for breast cancer therapy. Cancer Gene Ther 17, 235–243 (2010). https://doi.org/10.1038/cgt.2009.72

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  • DOI: https://doi.org/10.1038/cgt.2009.72

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